Yuan, J. & Yankner, B. A. Apoptosis in the nervous system. Nature 407, 802–809 (2000).
Degterev, A. et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol. 1, 112–119 (2005). This paper provides the first definition of necroptosis and insights into the functional role of necroptosis in acute neurological injuries.
Degterev, A. et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol. 4, 313–321 (2008). This paper demonstrates RIPK1 kinase activity as the target of Nec-1 and the role of RIPK1 as a key mediator of necroptosis.
Ofengeim, D. & Yuan, J. Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nat. Rev. Mol. Cell Biol. 14, 727–736 (2013).
Weinlich, R., Oberst, A., Beere, H. M. & Green, D. R. Necroptosis in development, inflammation and disease. Nat. Rev. Mol. Cell Biol. 18, 127–136 (2017).
Shan, B., Pan, H., Najafov, A. & Yuan, J. Necroptosis in development and diseases. Genes Dev. 32, 327–340 (2018).
Mullard, A. Microglia-targeted candidates push the Alzheimer drug envelope. Nat. Rev. Drug Discov. 17, 303–305 (2018).
Weisel, K. et al. Randomized clinical study of safety, pharmacokinetics, and pharmacodynamics of RIPK1 inhibitor GSK2982772 in healthy volunteers. Pharmacol. Res. Perspect. 5, e00365 (2017).
Yuan, J. & Horvitz, H. R. A first insight into the molecular mechanisms of apoptosis. Cell 116 (Suppl. 2), S53–S56 (2004).
Conradt, B., Wu, Y. C. & Xue, D. Programmed cell death during Caenorhabditis elegans development. Genetics 203, 1533–1562 (2016).
Yuan, J., Shaham, S., Ledoux, S., Ellis, H. M. & Horvitz, H. R. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1β-converting enzyme. Cell 75, 641–652 (1993).
Gagliardini, V. et al. Prevention of vertebrate neuronal death by the crmA gene. Science 263, 826–828 (1994).
Degterev, A., Boyce, M. & Yuan, J. A decade of caspases. Oncogene 22, 8543–8567 (2003).
Hyman, B. T. & Yuan, J. Apoptotic and non-apoptotic roles of caspases in neuronal physiology and pathophysiology. Nat. Rev. Neurosci. 13, 395–406 (2012).
Schafer, Z. T. & Kornbluth, S. The apoptosome: physiological, developmental, and pathological modes of regulation. Dev. Cell 10, 549–561 (2006).
Strasser, A., Jost, P. J. & Nagata, S. The many roles of FAS receptor signaling in the immune system. Immunity 30, 180–192 (2009).
Tummers, B. & Green, D. R. Caspase-8: regulating life and death. Immunol. Rev. 277, 76–89 (2017).
Kumar, S., van Raam, B. J., Salvesen, G. S. & Cieplak, P. Caspase cleavage sites in the human proteome: CaspDB, a database of predicted substrates. PLOS ONE 9, e110539 (2014).
Kalb, R. The protean actions of neurotrophins and their receptors on the life and death of neurons. Trends Neurosci. 28, 5–11 (2005).
Putcha, G. V., Deshmukh, M. & Johnson, E. M. Jr. Inhibition of apoptotic signaling cascades causes loss of trophic factor dependence during neuronal maturation. J. Cell Biol. 149, 1011–1018 (2000).
Kuida, K. et al. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 384, 368–372 (1996).
Kuida, K. et al. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94, 325–337 (1998).
Krajewska, M. et al. Dynamics of expression of apoptosis-regulatory proteins Bid, Bcl-2, Bcl-X, Bax and Bak during development of murine nervous system. Cell Death Differ. 9, 145–157 (2002).
Troy, C. M., Akpan, N. & Jean, Y. Y. Regulation of caspases in the nervous system implications for functions in health and disease. Prog. Mol. Biol. Transl Sci. 99, 265–305 (2011).
Kole, A. J., Annis, R. P. & Deshmukh, M. Mature neurons: equipped for survival. Cell Death Dis. 4, e689 (2013).
Sarosiek, K. A. et al. Developmental regulation of mitochondrial apoptosis by c-Myc governs age- and tissue-specific sensitivity to cancer therapeutics. Cancer Cell 31, 142–156 (2017).
Kole, A. J., Swahari, V., Hammond, S. M. & Deshmukh, M. miR-29b is activated during neuronal maturation and targets BH3-only genes to restrict apoptosis. Genes Dev. 25, 125–130 (2011).
Wright, K. M., Smith, M. I., Farrag, L. & Deshmukh, M. Chromatin modification of Apaf-1 restricts the apoptotic pathway in mature neurons. J. Cell Biol. 179, 825–832 (2007).
Perrelet, D. et al. Motoneuron resistance to apoptotic cell death in vivo correlates with the ratio between X-linked inhibitor of apoptosis proteins (XIAPs) and its inhibitor, XIAP-associated factor 1. J. Neurosci. 24, 3777–3785 (2004).
Tarkowski, E., Blennow, K., Wallin, A. & Tarkowski, A. Intracerebral production of tumor necrosis factor-α, a local neuroprotective agent, in Alzheimer disease and vascular dementia. J. Clin. Immunol. 19, 223–230 (1999).
Tarkowski, E., Andreasen, N., Tarkowski, A. & Blennow, K. Intrathecal inflammation precedes development of Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry 74, 1200–1205 (2003).
Lu, C. H. et al. Systemic inflammatory response and neuromuscular involvement in amyotrophic lateral sclerosis. Neurol. Neuroimmunol. Neuroinflamm. 3, e244 (2016).
Tateishi, T. et al. CSF chemokine alterations related to the clinical course of amyotrophic lateral sclerosis. J. Neuroimmunol. 222, 76–81 (2010).
Nagatsu, T., Mogi, M., Ichinose, H. & Togari, A. Cytokines in Parkinson’s disease. J. Neural Transm. Suppl. 58, 143–151 (2000).
Sharief, M. K. & Hentges, R. Association between tumor necrosis factor-α and disease progression in patients with multiple sclerosis. N. Engl. J. Med. 325, 467–472 (1991).
Habbas, S. et al. Neuroinflammatory TNFα impairs memory via astrocyte signaling. Cell 163, 1730–1741 (2015).
Walczak, H. Death receptor-ligand systems in cancer, cell death, and inflammation. Cold Spring Harb. Perspect. Biol. 5, a008698 (2013).
Martin-Villalba, A. et al. Therapeutic neutralization of CD95-ligand and TNF attenuates brain damage in stroke. Cell Death Differ. 8, 679–686 (2001).
Hovelmeyer, N. et al. Apoptosis of oligodendrocytes via Fas and TNF-R1 is a key event in the induction of experimental autoimmune encephalomyelitis. J. Immunol. 175, 5875–5884 (2005).
Nitsch, R. et al. Human brain-cell death induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL). Lancet 356, 827–828 (2000).
Uberti, D. et al. TRAIL is expressed in the brain cells of Alzheimer’s disease patients. Neuroreport 15, 579–581 (2004).
Cannella, B., Gaupp, S., Omari, K. M. & Raine, C. S. Multiple sclerosis: death receptor expression and oligodendrocyte apoptosis in established lesions. J. Neuroimmunol. 188, 128–137 (2007).
Christofferson, D. E. et al. A novel role for RIP1 kinase in mediating TNFα production. Cell Death Dis. 3, e320 (2012).
Jouan-Lanhouet, S. et al. TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation. Cell Death Differ. 19, 2003–2014 (2012).
Siegmund, D., Lang, I. & Wajant, H. Cell death-independent activities of the death receptors CD95, TRAILR1, and TRAILR2. FEBS J. 284, 1131–1159 (2017).
Probert, L. TNF and its receptors in the CNS: the essential, the desirable and the deleterious effects. Neuroscience 302, 2–22 (2015).
Srinivasan, K. et al. Untangling the brain’s neuroinflammatory and neurodegenerative transcriptional responses. Nat. Commun. 7, 11295 (2016).
Zhang, Y. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929–11947 (2014).
Hsu, H., Huang, J., Shu, H. B., Baichwal, V. & Goeddel, D. V. TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity 4, 387–396 (1996).
Micheau, O. & Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181–190 (2003).
Cho, Y. S. et al. Phosphorylation-driven assembly of the RIP1–RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112–1123 (2009).
Sun, L. et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148, 213–227 (2012).
Wang, H. et al. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol. Cell 54, 133–146 (2014).
Dondelinger, Y. et al. MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. Cell Rep. 7, 971–981 (2014).
Amin, P. et al. Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis. Proc. Natl Acad. Sci. USA 115, E5944–E5953 (2018).
Bertrand, M. J. et al. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol. Cell 30, 689–700 (2008).
Chen, Z. J. Ubiquitination in signaling to and activation of IKK. Immunol. Rev. 246, 95–106 (2012).
Geng, J. et al. Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis. Nat. Commun. 8, 359 (2017).
Dondelinger, Y. et al. NF-κB-independent role of IKKα/IKKβ in preventing RIPK1 kinase-dependent apoptotic and necroptotic cell death during TNF signaling. Mol. Cell 60, 63–76 (2015).
Jaco, I. et al. MK2 phosphorylates RIPK1 to prevent TNF-induced cell death. Mol. Cell 66, 698–710 (2017).
Menon, M. B. et al. p38MAPK/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection. Nat. Cell Biol. 19, 1248–1259 (2017).
Elliott, P. R. et al. SPATA2 links CYLD to LUBAC, activates CYLD, and controls LUBAC signaling. Mol. Cell 63, 990–1005 (2016).
Kupka, S. et al. SPATA2-mediated binding of CYLD to HOIP enables CYLD recruitment to signaling complexes. Cell Rep. 16, 2271–2280 (2016).
Schlicher, L. et al. SPATA2 promotes CYLD activity and regulates TNF-induced NF-κB signaling and cell death. EMBO Rep. 17, 1485–1497 (2016).
Wei, R. et al. SPATA2 regulates the activation of RIPK1 by modulating linear ubiquitination. Genes Dev. 31, 1162–1176 (2017).
Kovalenko, A. et al. The tumour suppressor CYLD negatively regulates NF-κB signalling by deubiquitination. Nature 424, 801–805 (2003).
Trompouki, E. et al. CYLD is a deubiquitinating enzyme that negatively regulates NF-κB activation by TNFR family members. Nature 424, 793–796 (2003).
Draber, P. et al. LUBAC-recruited CYLD and A20 regulate gene activation and cell death by exerting opposing effects on linear ubiquitin in signaling complexes. Cell Rep. 13, 2258–2272 (2015).
Hitomi, J. et al. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 135, 1311–1323 (2008).This paper describes a genome-wide siRNA screen for genes that regulate necroptosis.
Berger, S. B. et al. Cutting edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. J. Immunol. 192, 5476–5480 (2014).
Rahighi, S. et al. Specific recognition of linear ubiquitin chains by NEMO is important for NF-κB activation. Cell 136, 1098–1109 (2009).
Hadian, K. et al. NF-κB essential modulator (NEMO) interaction with linear and Lys-63 ubiquitin chains contributes to NF-κB activation. J. Biol. Chem. 286, 26107–26117 (2011).
Nanda, S. K. et al. Polyubiquitin binding to ABIN1 is required to prevent autoimmunity. J. Exp. Med. 208, 1215–1228 (2011).
Nakazawa, S. et al. Linear ubiquitination is involved in the pathogenesis of optineurin-associated amyotrophic lateral sclerosis. Nat. Commun. 7, 12547 (2016).
Ito, Y. et al. RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science 353, 603–608 (2016). This paper provides the first genetic connection between ALS and necroptosis.
Dziedzic, S. A. et al. ABIN-1 regulates RIPK1 activation by linking Met1 ubiquitylation with Lys63 deubiquitylation in TNF–RSC. Nat. Cell Biol. 20, 58–68 (2018). This paper describes the role of ABIN1, a ubiquitin-binding protein implicated in ALS and schizophrenia, in inhibiting the activation of RIPK1 and necroptosis.
Li, F. et al. Structural insights into the ubiquitin recognition by OPTN (optineurin) and its regulation by TBK1-mediated phosphorylation. Autophagy 14, 66–79 (2018).
Vlantis, K. et al. NEMO prevents RIP kinase 1-mediated epithelial cell death and chronic intestinal inflammation by NF-κB-dependent and -independent functions. Immunity 44, 553–567 (2016).
Xu, D. et al. TBK1 suppresses RIPK1-driven apoptosis and inflammation during development and in aging. Cell 174, 1477–1491 (2018). This paper reveals the molecular insights by which the reduced levels of TAK1, a key suppressor of RIPK1, in ageing of human brains cooperates with the haploinsufficiency of TBK1 to promote the onset of ALS.
Harhaj, E. W. & Dixit, V. M. Regulation of NF-κB by deubiquitinases. Immunol. Rev. 246, 107–124 (2012).
Vucic, D., Dixit, V. M. & Wertz, I. E. Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death. Nat. Rev. Mol. Cell Biol. 12, 439–452 (2011).
Wertz, I. E. et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling. Nature 430, 694–699 (2004).
Bosanac, I. et al. Ubiquitin binding to A20 ZnF4 is required for modulation of NF-κB signaling. Mol. Cell 40, 548–557 (2010).
Shembade, N., Ma, A. & Harhaj, E. W. Inhibition of NF-κB signaling by A20 through disruption of ubiquitin enzyme complexes. Science 327, 1135–1139 (2010).
McLaughlin, R. L. et al. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia. Nat. Commun. 8, 14774 (2017).
Lin, Y., Devin, A., Rodriguez, Y. & Liu, Z. G. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev. 13, 2514–2526 (1999).
Meng, H. et al. Death-domain dimerization-mediated activation of RIPK1 controls necroptosis and RIPK1-dependent apoptosis. Proc. Natl Acad. Sci. USA 115, E2001–E2009 (2018).
Varfolomeev, E. E. et al. Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9, 267–276 (1998).
Yeh, W. C. et al. FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 279, 1954–1958 (1998).
Dillon, C. P. et al. RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell 157, 1189–1202 (2014).
Rickard, J. A. et al. RIPK1 regulates RIPK3–MLKL-driven systemic inflammation and emergency hematopoiesis. Cell 157, 1175–1188 (2014).
Ofengeim, D. et al. Activation of necroptosis in multiple sclerosis. Cell Rep. 10, 1836–1849 (2015). This paper provides the first insight into the involvement and mechanism of RIPK1-mediated necroptosis in MS and the role of necroptosis in mediating oligodendrocyte cell death.
Micheau, O., Lens, S., Gaide, O., Alevizopoulos, K. & Tschopp, J. NF-κB signals induce the expression of c-FLIP. Mol. Cell. Biol. 21, 5299–5305 (2001).
Rehker, J. et al. Caspase-8, association with Alzheimer’s disease and functional analysis of rare variants. PLOS ONE 12, e0185777 (2017).
Gonzalvez, F. et al. TRAF2 sets a threshold for extrinsic apoptosis by tagging caspase-8 with a ubiquitin shutoff timer. Mol. Cell 48, 888–899 (2012).
Conforti, L., Gilley, J. & Coleman, M. P. Wallerian degeneration: an emerging axon death pathway linking injury and disease. Nat. Rev. Neurosci. 15, 394–409 (2014).
Zhou, T. et al. Implications of white matter damage in amyotrophic lateral sclerosis (review). Mol. Med. Rep. 16, 4379–4392 (2017).
Adalbert, R. & Coleman, M. P. Review: axon pathology in age-related neurodegenerative disorders. Neuropathol. Appl. Neurobiol. 39, 90–108 (2013).
Raff, M. C., Whitmore, A. V. & Finn, J. T. Axonal self-destruction and neurodegeneration. Science 296, 868–871 (2002).
Wang, J. T., Medress, Z. A. & Barres, B. A. Axon degeneration: molecular mechanisms of a self-destruction pathway. J. Cell Biol. 196, 7–18 (2012).
Waller, A. Experiments on the section of the glossopharyngeal and hypoglossal nerves of the frog, and observations of the alterations produced thereby in the structure of their primitive fibres. Phil. Trans. R. Soc. 140, 423–429 (1850).
Vargas, M. E. & Barres, B. A. Why is Wallerian degeneration in the CNS so slow? Annu. Rev. Neurosci. 30, 153–179 (2007).
Trapp, B. D. & Nave, K. A. Multiple sclerosis: an immune or neurodegenerative disorder? Annu. Rev. Neurosci. 31, 247–269 (2008).
Butts, B. D., Houde, C. & Mehmet, H. Maturation-dependent sensitivity of oligodendrocyte lineage cells to apoptosis: implications for normal development and disease. Cell Death Differ. 15, 1178–1186 (2008).
Yoshikawa, M. et al. Discovery of 7-oxo-2,4,5,7-tetrahydro-6 H-pyrazolo[3,4- c]pyridine derivatives as potent, orally available, and brain-penetrating receptor interacting protein 1 (RIP1) kinase inhibitors: analysis of structure–kinetic relationships. J. Med. Chem. 61, 2384–2409 (2018).
Dadon-Nachum, M., Melamed, E. & Offen, D. The “dying-back” phenomenon of motor neurons in ALS. J. Mol. Neurosci. 43, 470–477 (2011).
Fischer, L. R. & Glass, J. D. Axonal degeneration in motor neuron disease. Neurodegener. Dis 4, 431–442 (2007).
Sasaki, S. & Maruyama, S. Increase in diameter of the axonal initial segment is an early change in amyotrophic lateral sclerosis. J. Neurol. Sci. 110, 114–120 (1992).
Kang, S. H. et al. Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat. Neurosci. 16, 571–579 (2013).
Re, D. B. et al. Necroptosis drives motor neuron death in models of both sporadic and familial ALS. Neuron 81, 1001–1008 (2014).
Exner, N., Lutz, A. K., Haass, C. & Winklhofer, K. F. Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J. 31, 3038–3062 (2012).
Iannielli, A. et al. Pharmacological inhibition of necroptosis protects from dopaminergic neuronal cell death in Parkinson’s disease models. Cell Rep. 22, 2066–2079 (2018).
Wu, J. R. et al. Necrostatin-1 protection of dopaminergic neurons. Neural Regen Res. 10, 1120–1124 (2015).
Vitner, E. B. et al. RIPK3 as a potential therapeutic target for Gaucher’s disease. Nat. Med. 20, 204–208 (2014). This paper demonstrates the role of RIPK3 and necroptosis in GD.
Ransohoff, R. M. How neuroinflammation contributes to neurodegeneration. Science 353, 777–783 (2016).
Chen, H., Kankel, M. W., Su, S. C., Han, S. W. S. & Ofengeim, D. Exploring the genetics and non-cell autonomous mechanisms underlying ALS/FTLD. Cell Death Differ. 25, 646–660 (2018).
Zhang, B. et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell 153, 707–720 (2013).
Efthymiou, A. G. & Goate, A. M. Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk. Mol. Neurodegener. 12, 43 (2017).
Zhu, K. et al. Necroptosis promotes cell-autonomous activation of proinflammatory cytokine gene expression. Cell Death Dis. 9, 500 (2018).
Kigerl, K. A. et al. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J. Neurosci. 29, 13435–13444 (2009).
Mandrekar-Colucci, S. & Landreth, G. E. Microglia and inflammation in Alzheimer’s disease. CNS Neurol. Disord. Drug Targets 9, 156–167 (2010).
Collins, J. S. et al. Association of a haplotype for tumor necrosis factor in siblings with late-onset Alzheimer disease: the NIMH Alzheimer Disease Genetics Initiative. Am. J. Med. Genet. 96, 823–830 (2000).
He, P. et al. Deletion of tumor necrosis factor death receptor inhibits amyloid β generation and prevents learning and memory deficits in Alzheimer’s mice. J. Cell Biol. 178, 829–841 (2007).
Caccamo, A. et al. Necroptosis activation in Alzheimer’s disease. Nat. Neurosci. 20, 1236–1246 (2017). This paper provides human pathological evidence for the role of necroptosis in AD.
Ofengeim, D. et al. RIPK1 mediates a disease-associated microglial response in Alzheimer’s disease. Proc. Natl Acad. Sci. USA 114, E8788–E8797 (2017). This paper demonstrates the role of RIPK1 in mediating the microglial inflammatory response in AD.
Degterev, A., Maki, J. L. & Yuan, J. Activity and specificity of necrostatin-1, small-molecule inhibitor of RIP1 kinase. Cell Death Differ. 20, 366 (2013).
Yang, S. H. et al. Nec-1 alleviates cognitive impairment with reduction of Aβ and tau abnormalities in APP/PS1 mice. EMBO Mol. Med. 9, 61–77 (2017).
Papassotiropoulos, A. et al. Cholesterol 25-hydroxylase on chromosome 10q is a susceptibility gene for sporadic Alzheimer’s disease. Neurodegener. Dis 2, 233–241 (2005).
Jang, J. et al. 25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome. Nat. Commun. 7, 13129 (2016).
Li, J. et al. The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell 150, 339–350 (2012). This paper provides the structural evidence for the amyloid conformation of the necrosome in necroptosis.
Abdelhak, A., Weber, M. S. & Tumani, H. Primary progressive multiple sclerosis: putting together the puzzle. Front. Neurol. 8, 234 (2017).
Winblad, B. et al. Defeating Alzheimer’s disease and other dementias: a priority for European science and society. Lancet Neurol. 15, 455–532 (2016).
Deepa, S. S., Unnikrishnan, A., Matyi, S., Hadad, N. & Richardson, A. Necroptosis increases with age and is reduced by dietary restriction. Aging Cell 17, e12770 (2018).
Cirulli, E. T. et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347, 1436–1441 (2015).
Freischmidt, A., Muller, K., Ludolph, A. C., Weishaupt, J. H. & Andersen, P. M. Association of mutations in TBK1 with sporadic and familial amyotrophic lateral sclerosis and frontotemporal dementia. JAMA Neurol. 74, 110–113 (2017).
Mizushima, N. Autophagy in protein and organelle turnover. Cold Spring Harb. Symp. Quant. Biol. 76, 397–402 (2011).
Lipinski, M. M. et al. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer’s disease. Proc. Natl Acad. Sci. USA 107, 14164–14169 (2010).
Shibata, M. et al. Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1. J. Biol. Chem. 281, 14474–14485 (2006).
Saez, I. & Vilchez, D. The mechanistic links between proteasome activity, aging and age-related diseases. Curr. Genom. 15, 38–51 (2014).
Chiu, I. M. et al. Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice. Proc. Natl Acad. Sci. USA 106, 20960–20965 (2009).
Nuvolone, M. et al. Cystatin F is a biomarker of prion pathogenesis in mice. PLOS ONE 12, e0171923 (2017).
Ma, J. et al. Microglial cystatin F expression is a sensitive indicator for ongoing demyelination with concurrent remyelination. J. Neurosci. Res. 89, 639–649 (2011).
Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017).
Schetters, S. T. T., Gomez-Nicola, D., Garcia-Vallejo, J. J. & Van Kooyk, Y. Neuroinflammation: microglia and T cells get ready to tango. Front. Immunol. 8, 1905 (2017).
Gate, D., Rezai-Zadeh, K., Jodry, D., Rentsendorj, A. & Town, T. Macrophages in Alzheimer’s disease: the blood-borne identity. J. Neural Transm. 117, 961–970 (2010).
Weinlich, R. et al. Protective roles for caspase-8 and cFLIP in adult homeostasis. Cell Rep. 5, 340–348 (2013).
Rajput, A. et al. RIG-I RNA helicase activation of IRF3 transcription factor is negatively regulated by caspase-8-mediated cleavage of the RIP1 protein. Immunity 34, 340–351 (2011).
Dannappel, M. et al. RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513, 90–94 (2014).
Cuchet-Lourenco, D. et al. Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation. Science 361, 810–813 (2018).
Harris, P. A. et al. Discovery of small molecule RIP1 kinase inhibitors for the treatment of pathologies associated with necroptosis. ACS Med. Chem. Lett. 4, 1238–1243 (2013).
Polykratis, A. et al. Cutting edge: RIPK1 kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo. J. Immunol. 193, 1539–1543 (2014).
Shutinoski, B. et al. K45A mutation of RIPK1 results in poor necroptosis and cytokine signaling in macrophages, which impacts inflammatory responses in vivo. Cell Death Differ. 23, 1628–1637 (2016).
Duprez, L. et al. RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity 35, 908–918 (2011).
Liu, Y. et al. RIP1 kinase activity-dependent roles in embryonic development of Fadd-deficient mice. Cell Death Differ. 24, 1459–1469 (2017).
Najjar, M. et al. Structure guided design of potent and selective ponatinib-based hybrid inhibitors for RIPK1. Cell Rep. 10, 1850–1860 (2015).
Xie, T. et al. Structural basis of RIP1 inhibition by necrostatins. Structure 21, 493–499 (2013).
Harris, P. A. et al. Discovery of a first-in-class receptor interacting protein 1 (RIP1) kinase specific clinical candidate (GSK2982772) for the treatment of inflammatory diseases. J. Med. Chem. 60, 1247–1261 (2017).
Harris, P. A. et al. DNA-encoded library screening identifies benzo[b][1,4]oxazepin-4-ones as highly potent and monoselective receptor interacting protein 1 kinase inhibitors. J. Med. Chem. 59, 2163–2178 (2016).
Chen, Y. et al. Necrostatin-1 improves long-term functional recovery through protecting oligodendrocyte precursor cells after transient focal cerebral ischemia in mice. Neuroscience 371, 229–241 (2018).
Zhang, S. et al. Necrostatin-1 attenuates inflammatory response and improves cognitive function in chronic ischemic stroke mice. Medicines 3, E16 (2016).
King, M. D., Whitaker-Lea, W. A., Campbell, J. M., Alleyne, C. H. Jr & Dhandapani, K. M. Necrostatin-1 reduces neurovascular injury after intracerebral hemorrhage. Int. J. Cell Biol. 2014, 495817 (2014).
You, Z. et al. Necrostatin-1 reduces histopathology and improves functional outcome after controlled cortical impact in mice. J. Cereb. Blood Flow Metab. 28, 1564–1573 (2008).
Wang, Y. et al. Necroptosis inhibitor necrostatin-1 promotes cell protection and physiological function in traumatic spinal cord injury. Neuroscience 266, 91–101 (2014).
Do, Y. J. et al. A novel RIPK1 inhibitor that prevents retinal degeneration in a rat glaucoma model. Exp. Cell Res. 359, 30–38 (2017).
Rosenbaum, D. M. et al. Necroptosis, a novel form of caspase-independent cell death, contributes to neuronal damage in a retinal ischemia–reperfusion injury model. J. Neurosci. Res. 88, 1569–1576 (2010).
Kim, C. R., Kim, J. H., Park, H. L. & Park, C. K. Ischemia reperfusion injury triggers TNFα induced-necroptosis in rat retina. Curr. Eye Res. 42, 771–779 (2017).
Dvoriantchikova, G., Degterev, A. & Ivanov, D. Retinal ganglion cell (RGC) programmed necrosis contributes to ischemia–reperfusion-induced retinal damage. Exp. Eye Res. 123, 1–7 (2014).
Dong, K. et al. Necrostatin-1 protects photoreceptors from cell death and improves functional outcome after experimental retinal detachment. Am. J. Pathol. 181, 1634–1641 (2012).
Murakami, Y. et al. Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration. Cell Death Differ. 21, 270–277 (2014).
Cougnoux, A. et al. Necroptosis in Niemann–Pick disease, type C1: a potential therapeutic target. Cell Death Dis. 7, e2147 (2016).
Newton, K. et al. Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science 343, 1357–1360 (2014).
Lule, S. et al. Genetic inhibition of receptor interacting protein kinase-1 reduces cell death and improves functional outcome after intracerebral hemorrhage in mice. Stroke 48, 2549–2556 (2017).
Newton, K. et al. RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury. Cell Death Differ. 23, 1565–1576 (2016).
Kaiser, W. J. et al. RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition. Proc. Natl Acad. Sci. USA 111, 7753–7758 (2014).
Fan, H. et al. Reactive astrocytes undergo M1 microglia/macrophages-induced necroptosis in spinal cord injury. Mol. Neurodegener. 11, 14 (2016).
Liu, Z. M. et al. RIP3 deficiency protects against traumatic brain injury (TBI) through suppressing oxidative stress, inflammation and apoptosis: dependent on AMPK pathway. Biochem. Biophys. Res. Commun. 499, 112–119 (2018).
Trichonas, G. et al. Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis. Proc. Natl Acad. Sci. USA 107, 21695–21700 (2010).